SQA CfE Higher Human Biology Unit 4: Immunology and Public Health

Transcription

1 SCHOLAR Study Guide SQA CfE Higher Human Biology Unit 4: Immunology and Public Health Authored by: Eoin McIntyre Reviewed by: Sheena Haddow Previously authored by: Mike Cheung Eileen Humphrey Eoin McIntyre Jim McIntyre Heriot-Watt University Edinburgh EH14 4AS, United Kingdom.

2 First published 2014 by Heriot-Watt University. This edition published in 2014 by Heriot-Watt University SCHOLAR. Copyright 2014 Heriot-Watt University. Members of the SCHOLAR Forum may reproduce this publication in whole or in part for educational purposes within their establishment providing that no profit accrues at any stage, Any other use of the materials is governed by the general copyright statement that follows. All rights reserved. No part of this publication may be reproduced, stored in a retrieval system or transmitted in any form or by any means, without written permission from the publisher. Heriot-Watt University accepts no responsibility or liability whatsoever with regard to the information contained in this study guide. Distributed by Heriot-Watt University. SCHOLAR Study Guide Unit 4: SQA CfE Higher Human Biology 1. SQA CfE Higher Human Biology ISBN Printed and bound in Great Britain by Graphic and Printing Services, Heriot-Watt University, Edinburgh.

3 Acknowledgements Thanks are due to the members of Heriot-Watt University's SCHOLAR team who planned and created these materials, and to the many colleagues who reviewed the content. We would like to acknowledge the assistance of the education authorities, colleges, teachers and students who contributed to the SCHOLAR programme and who evaluated these materials. Grateful acknowledgement is made for permission to use the following material in the SCHOLAR programme: The Scottish Qualifications Authority for permission to use Past Papers assessments. The Scottish Government for financial support. All brand names, product names, logos and related devices are used for identification purposes only and are trademarks, registered trademarks or service marks of their respective holders.

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5 i Contents 1 Non-specific defences Introduction The immune system Non-specific defences - physical and chemical The inflammatory response Non-specific cellular responses Learning points Extended response question End of topic test Specific cellular defences Immune surveillance Clonal selection theory T- and B-lymphocytes The action of T-lymphocytes The action of B-lymphocytes Immunological memory Learning points Extended response question End of topic test The transmission and control of infectious diseases Infectious diseases caused by pathogens Methods of transmission of pathogens Control of spread of pathogens Epidemiological studies of infectious diseases Learning points Extended response question End of topic test Active immunisation Active immunisation and vaccination Herd Immunity Immunisation programmes The evasion of specific immune responses by pathogens Learning points Extended response question End of topic test End of unit test 81

6 ii CONTENTS Glossary 85 Answers to questions and activities 87 1 Non-specific defences Specific cellular defences The transmission and control of infectious diseases Active immunisation End of unit test

7 1 Topic 1 Non-specific defences Contents 1.1 Introduction The immune system Non-specific defences - physical and chemical The inflammatory response Inflammation The cellular basis of inflammation Non-specific cellular responses Phagocytes Natural killer (NK) cells Learning points Extended response question End of topic test Prerequisite knowledge You should already know about: defences against disease (phagocytosis, antibodies, vaccination); diseases (viruses, bacteria, fungi, parasites); hygiene (personal, sexual, food, water). Learning Objectives By the end of this topic, you should be able to: state that the body's capacity to protect itself against pathogens, some toxins and cancer cells is achieved by means of the immune system; describe the nature of the body's chemical and physical defences against pathogens; describe the inflammatory response; describe the non-specific cellular responses.

8 2 TOPIC 1. NON-SPECIFIC DEFENCES 1.1 Introduction If it were possible that an intelligent life-form from another planet in our galaxy could visit Earth, and that we could communicate with it, we might ask what it thought of the place. If we enquired about what it considered to be the dominant life-form, we might be surprised at the answer because it has been estimated that 90% of the energy processed by organisms on the planet is done so by bacteria. Likewise, the total biomass of bacteria on the planet is thought to exceed that of all other living things put together. With an average size of 1µm, they have found niches virtually everywhere, from the bedrock, to the clouds, the deep sea floor, and hot springs. And, of course, nine tenths of the cells within our bodies are bacteria. It may be a bit disconcerting to conceive of ourselves as habitats, but we are just that (and a very attractive one!) to bacteria and other microbes. Our tissues are warm and constantly bathed in nutrient- and oxygen-rich fluid, conditions which are perfect for microbes to thrive in. Much of this is true of all multicellular organisms, and so, to exist at all, they have had to evolve methods of countering colonisation by microbes. A common misconception is that all microbes are potential pathogens, but that is far from true. We could not live a healthy life without our varied and complex gut flora of bacteria, and trees could not absorb nutrients from the soil without the aid of the fungal threads attached to their roots. It should also be remembered that although we tend to think of bacteria in relation to infection, the heterotrophic organisms that test our defences come from all categories, so we have to be able to defend ourselves against viruses (e.g. flu), bacteria (e.g. pneumonia), fungi (e.g. athlete's foot), protozoans (e.g. malaria), and even quite large animals (e.g. tapeworms). We will leave the discussion about whether viruses are alive to another time. This unit addresses the natural defences that our bodies have against microbial attack in the form of our immune system, and the precautions that human societies put in place to counter the spread of disease in the shape of public health measures. 1.2 The immune system Learning Objective By the end of this section, you should be able to: state that the function of the immune system is to protect the body against pathogens, some toxins and cancer cells. The body's capacity to protect itself against pathogens, some toxins and cancer cells is achieved by means of the immune system. We have three lines of defence against attack by pathogens. 1. The first line of defence is non-specific - an external barrier of skin and mucous membranes and the secretions that they produce. The skin provides a physical barrier of dry, dead cells and mildly acidic conditions. Areas of the body which

9 TOPIC 1. NON-SPECIFIC DEFENCES 3 are not protected by this barrier, such as the eyes and mouth, have secretions in the form of tears and saliva, which contain a variety of antimicrobial enzymes, e.g. lysozyme which degrades bacterial cell walls. 2. The second line of defence is also non-specific, and comes into play when the first line of defence is breached and an intruder, such as a bacterium, gets into the body tissues. The intruder produces chemical signals that are detected by a variety of white blood cells which will attack it in a number of ways, e.g. neutrophils and macrophages which engulf the invading cells, and natural killer cells (NK cells) which release chemicals that cause their death. An area of inflammation indicates that the second line of defence has been deployed. 3. The third line of defence, the specific immune response (to be covered in Topic 2) comes into play at the same time as the second line of defence. Here, the immune system directly targets the invader, which can be any organism or substance that carries foreign molecules. Immunity is the ability of the body to resist or overcome an infection by a pathogen and can be either innate or acquired. Innate immunity is inborn, non-specific, and does not change over time. Examples include: phagocytosis by phagocytes; skin epithelial cells; mucus membranes of the lungs and gut; ciliated cells of the respiratory tract; lysozyme in tears. Acquired immunity develops throughout a person's life time and can be induced either naturally or artificially. It involves another group of white blood cells, lymphocytes, which respond to marker chemicals on the surface of the foreign cells called antigens, producing antibodies against them. A second response is the production of memory cells, which enable the immune system to react more quickly and vigorously to reinfection by pathogens. The immune system: Questions Q1: What is the function of the immune system? Q2: List two examples of non-specific first line of defence against diseases. Q3: What is the function of the lysozyme in tears? Q4: Explain the term 'innate immunity' and list two examples. Q5: What is a phagocyte?

10 4 TOPIC 1. NON-SPECIFIC DEFENCES 1.3 Non-specific defences - physical and chemical Learning Objective By the end of this section, you should be able to: give examples of the body's chemical and physical defences against pathogens; explain that epithelial cells form a physical barrier and produce secretions against infection. You should remember from Unit 1 that epithelial cells provide the inner and outer linings of body cavities, for example the stomach and the urinary tract. They act as the barrier between the external environment and the body tissues. The skin is considered to be the first line of defence for the human body. Its structure ensures that very few microorganisms can penetrate unless it is damaged. In addition, the secretion of antimicrobial chemicals by the skin and tear glands offers additional protection. The outermost part of the skin, or epidermis, is a multilayered tissue. At its base are stem cells which divide to continually replace the layers above it. As they move from the base towards the surface, the cells gradually change their structure to give the epidermis its tough elastic properties. The outer layer consists of dead cells, which are regularly sloughed off as a result of friction with the environment. These are dry and provide an environment which is inhospitable to microbes. Associated with the hair follicles on the skin are the sebaceous glands, which secrete the waxy sebum that keeps the skin supple and contains fatty acids which have antimicrobial properties. Similarly, earwax contains chemicals which inhibit the growth of pathogenic bacteria and fungi. Certain types of epithelial cells secrete fluids that are necessary for processes such as digestion, protection, excretion of waste products and the regulation of the metabolic processes of the body, e.g. the goblet cells which secrete mucus. Epithelial tissues containing goblet cells

11 TOPIC 1. NON-SPECIFIC DEFENCES 5 Some epithelial tissues are specialised to secrete specific substances, such as enzymes, hormones and lubricating fluids, to defend against infections. The goblet cells in the trachea secrete mucus which, being a sticky substance, is able to adhere to foreign particles, thus holding them on the surface. This adhesion allows the cilia which line the bronchi to sweep the mucus, with its entrapped particles, up into the pharynx where it is swallowed. Antimicrobial chemicals are also found in the mucus, secreted by the epithelial linings of the respiratory and upper gastrointestinal tracts. The body can also provide other physical and chemical defences: tiny hairs at the entrance to the nose; cough and sneeze reflexes; acid secretions which kill microbes, e.g. stomach; the so-called 'friendly' bacteria which are the many harmless microbes normally found on the skin and epithelial linings that are exposed to the external environment - by means of a variety of mechanisms, these microbes can suppress the growth of other potentially more dangerous and harmful ones. Non-specific defences - physical and chemical: Questions Q6: State two ways in which the skin is a physical barrier to microbes. Q7: State two ways in which the epithelium presents a chemical barrier to microbes.

12 6 TOPIC 1. NON-SPECIFIC DEFENCES 1.4 The inflammatory response Learning Objective By the end of this section, you should be able to: state that mast cells release histamine; explain that histamine causes vasodilation and increases capillary permeability; state that mast cells also secrete cytokines which act as signalling molecules; explain that the increased blood flow and the secretion of cytokines lead to: accumulation of phagocytes such as macrophages and neutrophils; delivery of antimicrobial proteins and clotting elements to the site of infection/damage Inflammation We are all familiar with the reddening which follows the infection of a scratch, bite or sting. However, in medical terms, inflammation is a more complex issue. It is a response of the immune system to an infection or irritation. Some 2000 years ago, inflammation was characterised into: rubor - redness; calor - heat; tumour - swelling; dolo - pain; functio laesa, the fifth sign of inflammation, which results in the dysfunction of the organs involved.

13 TOPIC 1. NON-SPECIFIC DEFENCES 7 Main events in the inflammatory response 10 min The cellular basis of inflammation The main purpose of the complex inflammatory process is to bring fluids, proteins and cells from the blood to the damaged tissues. It should be remembered that the fluid that bathes the cells of the body's tissues and organs lacks most of the proteins and cells that are found in the blood because they are not able to pass through the capillary walls. Thus, to combat damage and infections, there must be mechanisms which allow these proteins and cells to move out of the blood circulation and into the surrounding tissue fluid. This process can be broken down into six stages. Stage 1: The action of mast cells Mast cells are found in connective tissue, where they cluster around blood vessels and nerves. They are most common where our tissues meet the outside world, e.g. skin, gut, mouth, eyes and nose. Although they resemble certain white blood cells and, like them, are produced by stem cells in the bone marrow, they are derived from a different cell line. Perhaps best known for mediating allergies, they also play a key role in protection against infection. They are activated by chemicals that are released during an infection or from damaged cells, as a result of which they release histamine in large quantities.

14 8 TOPIC 1. NON-SPECIFIC DEFENCES A mast cell Stage 2: Vasodilation and increased capillary permeability Histamine is a small, organic, nitrogenous molecule which has many roles in the body. In the inflammatory response, it stimulates the arterioles of the affected area to dilate, increasing blood flow into the capillary beds, and the walls of the capillaries to become more permeable, allowing plasma, proteins and white blood cells (neutrophils) to pass through. Within minutes of an injury, this is noticeable as a swelling and reddening of the area, and a feeling of heat. Stage 3: Secretion of cytokines The mast cells and the neutrophils also release a type of signalling compound called cytokines. Like histamine, these have a wide range of roles in the body, but in this case they act to attract another type of white blood cell, monocytes, to the area. Stage 4: Phagocytosis Once in the tissue, the neutrophils begin the removal of invading bacteria by phagocytosis. They are soon joined by the monocytes, which mature into macrophages and then clean up the damaged area by engulfing cell debris and bacteria by phagocytosis. After digestion is complete, the identifying surface molecules (antigens) of invading cells are transported to the surface of the macrophages where they assist the other cells of the immune system to develop protection against the invader. The term 'phagocyte' is used to refer to a general grouping which includes macrophages, neutrophils and mast cells, all of which are capable of phagocytosis, but which differ in other respects. Stage 5: The complement system The complement system is so-called because it helps, and indeed amplifies, the action of the phagocytes in combating infection. It comprises over 25 small proteins found in the blood, which are synthesised by the liver. These remain in an inactive form until stimulated by one of several triggers; in particular the cascade is triggered if cells which lack the surface proteins typical of the body are encountered.

15 TOPIC 1. NON-SPECIFIC DEFENCES 9 Activation of the first complement protein leads to activation of the second, which activates the third, and so on, resulting in a cascade effect. These substances have several basic functions, including enhancing phagocytosis, attracting macrophages and neutrophils, and rupturing the membranes of microbes. Stage 6: Clotting elements and the coagulation system The increased permeability of the capillary walls leads to an increased flow of proteins ('clotting elements') as well as white blood cells into the tissues, and a second cascade system (the 'coagulation system') becomes active. In the infected tissue, a chemical 'tissue factor' is released that initiates the cascade which results in the conversion of the soluble protein fibrinogen to insoluble fibrin. The fibrin strands form a web which helps to contain the infection and inflammation. The cellular basis of inflammation: Questions Q8: Where are mast cells found? Q9: State two effects of the histamine released by mast cells. Q10: Name the chemical signalling molecule which is released by mast cells and neutrophils. Q11: Which type of white blood cells are attracted by this chemical? Q12: By what process do these cells remove bacteria from the site of infection? Q13: Name the cascade system which delivers antimicrobial proteins to the infected site. Q14: Name the soluble and insoluble proteins at the end of the coagulation system.

16 10 TOPIC 1. NON-SPECIFIC DEFENCES 1.5 Non-specific cellular responses Learning Objective By the end of this section, you should be able to: state that the white blood cells involved in the non-specific response are phagocytes and natural killer (NK) cells; state that phagocytes and NK cells release cytokines; explain that cytokines stimulate the specific immune response; state that phagocytes recognise surface antigen molecules on pathogens; state that phagocytes destroy pathogens by phagocytosis; explain that phagocytosis is engulfing and digesting solid particles; state that NK cells induce pathogens to produce self-destructive enzymes; state that this process of induced self-destruction by enzymes is called apoptosis. The business of defending the body against foreign cells and molecules which have penetrated the first line of defence falls to certain types of white blood cell. In this section, we will consider the non-specific role of two groups: the phagocytes (monocytes and neutrophils) and natural killer (NK) cells Phagocytes The name 'phagocyte' is an umbrella term encompassing several types of white blood cell and mast cells; their common features include their origin in the bone marrow, their ability to move about (motility) and their ability to carry out phagocytosis.

17 TOPIC 1. NON-SPECIFIC DEFENCES 11 Phagocytosis: Steps 10 min The two most important phagocytes are the white blood cells: neutrophils and monocytes. A question to be asked is how do the phagocytes (and the complement system mentioned earlier) identify bacteria; what makes them stand out from the cells of the body itself? The answer lies in proteins located on the surface of the cell membrane. If a phagocyte encounters a cell which is lacking the protein markers typical of cells belonging to the body, then a response is triggered. Neutrophils Neutrophils make up two thirds of the white blood cells in the blood and are the main cells found in pus. They are attracted to the site of infection by the cytokines released by the damaged cells, arriving in large numbers within minutes. The neutrophils also release cytokines themselves, but their immediate effect is the engulfing of bacteria. Their lifespan is short, being only 5-7 days in the circulation, and 1-2 days at an infection site. This reflects the fact that they cannot replenish the digestive enzymes with which they break down ingested bacteria.

18 12 TOPIC 1. NON-SPECIFIC DEFENCES Once they have engulfed bacteria, the neutrophils express signal molecules on their cell membranes which identify them to the larger macrophages, which then consume them in turn. In addition, they secrete antimicrobial chemicals which kill bacteria by disrupting their cell walls. Monocytes Monocytes are the largest of the white blood cells; at up to 20µm they are nearly twice the size of neutrophils. They are much less common than neutrophils, making up only some 5% of the total white blood count. About half of the body's complement of monocytes is held in reserve in the spleen, the other half circulating in the blood and migrating into the tissues where they mature into macrophages capable of phagocytosis. Attracted by cytokines that are released by neutrophils and damaged cells, additional monocytes migrate from the blood to an infection site and turn into macrophages. They then begin to engulf damaged cells, bacteria and 'old' neutrophils. Unlike neutrophils, macrophages can live for several months. Also, they express the antigens of ingested bacteria on their outer membranes to help the other white blood cells of the immune system (lymphocytes) identify the invaders and produce specific antibodies to combat them. Phagocytes: Questions Q15: Name the chemical produced by phagocytes and NK cells. Q16: What is the function of this chemical? Q17: By what do phagocytes recognise pathogens? Q18: What is phagocytosis? Natural killer (NK) cells NK cells are attracted to the site of an infection (or a tumour) after about three days by the cytokines released by the damaged cells. They identify infected cells and tumour cells by the presence of certain key surface chemicals and then release two types of enzymes: perforin and a type of protease known as granzyme. The perforin causes pores to develop in the cell membrane of the target cell so that the granzyme can enter the cell and induce programmed cell death (apoptosis). The cell contains apoptosis pathways which allow it to self-destruct by enzyme action and thus be recycled in a controlled way; these pathways are activated by the granzymes and, critically, they also cause the destruction of the viruses in the cell. Like neutrophils, NK cells also secrete antimicrobial chemicals.

19 TOPIC 1. NON-SPECIFIC DEFENCES 13 Apoptosis: Steps Action of a natural killer cell 5 min Apart from their role in non-specific response, phagocytes and NK cells are also involved in the specific immune response (described later). After their action against invading pathogens, they then secrete interleukin, a cytokine that stimulates the specific immune response by activating T lymphocytes.

20 14 TOPIC 1. NON-SPECIFIC DEFENCES Natural killer (NK) cells: Questions Q19: What do the NK cells induce target cells to produce? Q20: What is the process of programmed self-destruction in cells called? 1.6 Learning points Summary Physical and chemical defences The function of the immune system is to protect the body against pathogens, some toxins and cancer cells. Give examples of the body's chemical and physical defences against pathogens, e.g. sebum secreted onto the skin contains fatty acids with antimicrobial properties; the dry outer layers of the epidermis create an environment hostile to pathogens. The inflammatory response Mast cells release histamine. Histamine causes vasodilation and increases capillary permeability. Mast cells also secrete cytokines which act as signalling molecules. The increased blood flow and the secretion of cytokines lead to: accumulation of phagocytes such as macrophages and neutrophils; delivery of antimicrobial proteins and clotting elements to the site of infection/damage. Non-specific cellular responses The white blood cells involved in the non-specific response are phagocytes and natural killer (NK) cells. Phagocytes and NK cells release cytokines. Cytokines stimulate the specific immune response. Phagocytes recognise surface antigen molecules on pathogens. Phagocytes destroy pathogens by phagocytosis. Phagocytosis is engulfing and digesting solid particles. NK cells induce pathogens to produce self-destructive enzymes. The process of induced self-destruction by enzymes is called apoptosis.

21 TOPIC 1. NON-SPECIFIC DEFENCES Extended response question The activity which follows presents an extended response question similar to the style that you will encounter in the examination. You should have a good understanding of the inflammatory response before attempting the question. You should give your completed answer to your teacher or tutor for marking, or try to mark it yourself using the suggested marking scheme. Extended response question: The inflammatory response Give an account of the inflammatory response. (8 marks) 1.8 End of topic test End of Topic 1 test Q21: Complete the sentences by matching the parts on the left and the right. (8 marks) The immune system protects the body against Sebum on the skin contains fatty acids with Pathogens find the dry outer layers of the skin to be Mast cells release Histamine causes Cytokines act as Increased blood flow leads to delivery of cytokines. a hostile environment. histamine. clotting elements. antimicrobial properties. pathogens. signalling molecules. Phagocytes are attracted by vasodilation. Q22: Complete the paragraphs by selecting words from the list. (10 marks) The white blood cells involved in the response are and natural killer ( ) cells. Both phagocytes and NK cells release which stimulate the specific immune response. Phagocytes target pathogens which they recognise by the molecules on their cell surface. They then destroy them by and digesting them in a process called. The NK cells release which induce infected cells and pathogens to produce the enzymes of pathways. Word list: antigen, apoptosis, cytokines, engulfing, enzymes, NK, non-specific, phagocytes, phagocytosis, self-destructive.

22 16 TOPIC 1. NON-SPECIFIC DEFENCES Q23: What is the function of the immune system? (1 mark) Q24: State two ways in which the skin prevents infection. (2 marks) Q25: Name the cells which release histamine. (1 mark) Q26: State the functions of histamine. (2 marks) Q27: Name the signalling molecules released by these cells. (1 mark) Q28: State the function of the signalling molecules. (1 mark) Q29: What is delivered by the increased blood flow to the site of infection? (2 marks) Q30: Name the two types of white blood cells involved in the non-specific response. (1 mark) Q31: How do phagocytes recognise pathogens? (1 mark) Q32: Describe the process of phagocytosis. (1 mark) Q33: What do NK cells induce infected cells and pathogens to produce? (1 mark) Q34: Name the process of programmed cell death. (1 mark)

23 17 Topic 2 Specific cellular defences Contents 2.1 Immune surveillance Clonal selection theory T- and B-lymphocytes The action of T-lymphocytes The action of B-lymphocytes Immunological memory Learning points Extended response question End of topic test Learning Objectives By the end of this topic, you should be able to: describe the immune surveillance system in terms of the cells involved and their functions; explain clonal selection theory and its role in the specific immune response; describe the functions of T- and B-lymphocytes; explain the role of immunological memory in the development of immunity.

24 18 TOPIC 2. SPECIFIC CELLULAR DEFENCES In the previous topic, the body's general response to invasion by pathogens or other damage was described. This topic deals with the very sophisticated system which allows the body, once it has met a particular pathogen, to respond very promptly and efficiently to a second (or later) invasion by that organism. 2.1 Immune surveillance Learning Objective By the end of this section, you should be able to: describe the role of white blood cells as constantly monitoring the tissues; explain that pathogens, and other foreign cells or materials, are recognised by their antigens, which are molecules on their surfaces that activate the immune system; state that cytokines are released when tissues are damaged or invaded; explain that cytokines attract specific white blood cells (monocytes) to the infected/damaged tissue; explain that some of these cells absorb pathogens and display fragments of their cell membranes on their surface. The immune system operates by means of the activities of several different types of cell. It responds to the presence of pathogens, and other foreign cells or materials which are recognised by their antigens; that is molecules on their surfaces which activate the immune system. The cells of the non-specific immune response are the mast cells, phagocytes and natural killer (NK) cells, whereas the specific immune response operates by means of the B- and T-lymphocytes. These cells, along with red blood cells (erythrocytes) and platelets (thrombocytes), are all produced by division of the multipotent stem cells in the red bone marrow (the haematopoietic stem cells). A simplified diagram of this family tree is shown below.

25 TOPIC 2. SPECIFIC CELLULAR DEFENCES 19 Haematopoiesis The haematopoietic stem cells give rise to two families of cells, namely those formed from the common myeloid progenitor, and those from the common lymphoid progenitor. The myeloid group includes red blood cells (erythrocytes), thrombocytes (platelets), mast cells and the various white blood cells involved in the non-specific response. Cells of the surveillance system The cells involved in the specific immune response, namely the T- and B-lymphocytes, belong to the lymphoid family. An exception is the natural killer (NK) cell which, though belonging to the lymphoid group, acts as part of the non-specific response. The cells associated with the non-specific response provide a surveillance system in the following ways: 1. mast cells are found within the tissues and respond within seconds to damage or infection by releasing histamine; 2. neutrophils, which circulate in the blood, enter the tissues when the histamine released by the mast cells causes increased blood flow to the affected tissue, increasing permeability of the capillary walls - they are attracted to the damaged area by chemical signals released by damaged cells; 3. the mast cells and neutrophils, as well as mopping up damaged cells and invading pathogens by phagocytosis, also release cytokines which attract monocytes to the tissue - these mature into macrophages which engulf damaged cells, pathogens, and any neutrophils which are signalling that they have themselves engulfed pathogens;

26 20 TOPIC 2. SPECIFIC CELLULAR DEFENCES 4. some of the macrophages present fragments of the cell membrane of engulfed pathogens on their own cell surface - these cells migrate to the lymph nodes where the pathogen fragments, carrying their unique antigens, activate the B- and T- lymphocytes which are stored there. Immune surveillance: Questions Q1: Name the cells of the nonspecific immune system which first respond to infection and are located within the tissues. Q2: Name the cells of the nonspecific immune system which first respond to infection and are located in the blood. Q3: Name the chemicals which attract monocytes to the damaged tissue. Q4: Where are the B- and T-lymphocytes stored? Q5: How do some of the cells that monocytes develop into identify pathogens to the specific immune system? 2.2 Clonal selection theory Learning Objective By the end of this section, you should be able to: state that clonal selection theory explains the way in which lymphocytes are developed to respond to specific antigens which invade the body; state that lymphocytes have a single type of receptor on the cell membrane which is specific to one antigen; explain how antigen binding leads to repeated lymphocyte division, which results in a clonal population of lymphocytes. The Theory Clonal Selection Theory was proposed in 1957 by an Australian medical researcher, Frank Macfarlane Burnet, as an answer to the question: how do we account for the immune system's ability to produce antibodies in response to new antigens? A radical feature of the theory was that the body actually has lymphocytes carrying antibodies for antigens which it has never encountered. Given the vast range of potential

27 TOPIC 2. SPECIFIC CELLULAR DEFENCES 21 antigens that exists, this seems highly improbable. However, subsequent research, most recently into the genes controlling the production of antibodies, has confirmed the validity of Burnet's concept and, indeed, it underpins our whole understanding of the operation of the adaptive immune system. Several Nobel Prizes have been awarded for research in this field. The steps in the development of lymphocytes which carry receptors specific to one antigen is summarised below. As the process is similar in the B- and T-lymphocytes (covered in the next section), they have not been dealt with separately here. Clonal selection theory: Steps 1. In the red bone marrow, haematopoietic stem cells divide to produce daughter cells. 2. As a result of genetic rearrangement, during differentiation these immature lymphocytes each develop a different antigen receptor on their cell membranes. 3. Those immature lymphocytes which carry a receptor that will bind with an antigen from the body s own tissues are destroyed in the bone marrow. 4. The lymphocytes carrying other antigen receptors are released from the bone marrow and move through the circulatory system to the lymph glands or thymus gland where they mature into inactive lymphocytes. 5. Most of these inactive lymphocytes will never encounter an antigen to match their receptor. 6. Inactive lymphocytes which do meet an antigen matching their receptor become activated and divide to produce many clones of themselves.

28 22 TOPIC 2. SPECIFIC CELLULAR DEFENCES Genetic background to antibody variability To understand better how the variability of the receptors (and the antibodies to which they are related) arises, it is necessary to delve a little into the genetic control of antibody production. Antibodies (also known as immunoglobulins) exist in two forms, one which is bound to the outer surface of the cell membrane of lymphocytes, and another which is secreted by these cells and exists as soluble protein in the blood plasma, tissue fluid and lymph. These antibody molecules are made up of four basic polypeptide chains that are coded for by three genes which are located on three different chromosomes. Each of these genes is composed of many segments. In the course of differentiation, these segments are subject to such a degree of alternative splicing during DNA transcription that there are approximately unique potential antibody molecules that could be expressed on the cell membrane. Only one of these would be found on any particular lymphocyte. The development of immunity The receptors on the inactive lymphocytes act like antibodies in that they specifically bind to a single antigen molecule. If this happens, then a series of changes are triggered in the lymphocyte. The combination of gene segments becomes fixed, and only that combination will be used to produce antibodies by that cell and its clones. The activated lymphocyte begins to divide to produce two types of cloned daughter cell: 1. plasma cells, which have extensive folded membrane layers in the cytoplasm that are covered with ribosomes to produce large quantities of the polypeptides which will be formed into antibodies in the Golgi apparatus; 2. memory cells, which remain in the lymph glands ready to be activated by subsequent encounters with the same antigen - during the first exposure to the antigen, e.g. during an infection, these cells undergo a considerable degree of minor mutations and the mutants with the best match of receptor to antigen are maintained, the being remainder destroyed - during a second infection, these cells produce a much more rapid and effective response. Clonal selection theory: Questions Q6: Put the steps from clonal selection theory into the correct order. Those immature lymphocytes, which carry a receptor that will bind with an antigen from the body's own tissues, are destroyed in the bone marrow. As a result of genetic rearrangement, during differentiation these immature lymphocytes each develop a different antigen receptor on their cell membranes. Inactive lymphocytes, which do meet an antigen matching their receptor, become activated and divide to produce many clones of themselves. Most of these inactive lymphocytes will never encounter an antigen to match their receptor. In the red bone marrow, haematopoietic stem cells divide to produce daughter cells. The lymphocytes that carry other antigen receptors are released from the bone marrow and move through the circulatory system to the lymph glands or thymus gland where they mature into inactive lymphocytes.

29 TOPIC 2. SPECIFIC CELLULAR DEFENCES 23 Q7: What does clonal selection theory explain? Q8: To how many different types of antigen do the receptors on each lymphocyte respond? 2.3 T- and B-lymphocytes Learning Objective By the end of this section, you should be able to: state that lymphocytes respond specifically to antigens on foreign cells, cells infected by pathogens and toxins released by pathogens; state that T-lymphocytes have specific surface proteins that allow them to distinguish between the surface molecules of the body's own cells and cells with foreign molecules on their surface; explain that autoimmune diseases arise as a result of a failure of immune system regulation, leading to a response by T-lymphocytes to self antigens; state that activated B-lymphocytes secrete antibodies into the blood and lymph; explain that allergies are a hypersensitive B-lymphocyte response to an antigen that is normally harmless. Distinguishing 'self-' from 'non-self' antigens As was described in Section 2.1, T- and B-lymphocytes are produced by the haematopoietic stem cells in the red bone marrow and they belong to the lymphoid group of cells. Both have the ability to respond to specific antigens, which may be: part of foreign cells; attached to the surface of cells which are infected by pathogens; or toxins (biologically produced poisons). This response to specific antigens is achieved by the cells having receptor proteins on their cell membranes which are only capable of binding with that antigen. Given that lymphocytes which carry receptors for the body's own ('self') antigens are eliminated before they can leave the bone marrow, this enables the lymphocytes collectively to distinguish between the foreign ('non-self') antigens and those of the body's own cells. The mechanism of antigen binding and the subsequent response of the cell are the main differences between actions of the T- and B-lymphocytes. Once released from the bone marrow, T- and B-lymphocytes differ in the locations where they mature. For T-lymphocytes it is the thymus gland which is found in front of the heart underneath the sternum (breast bone); for B-lymphocytes it is small patches of cells in

30 24 TOPIC 2. SPECIFIC CELLULAR DEFENCES the extensive network of lymph glands associated with the intestine. Once mature, the lymphocytes may be found throughout the body, but in particular they locate in the lymph glands and the spleen, where they can readily detect foreign antigens in the lymph and blood which are filtered through these organs. Autoimmune disease An autoimmune disease is a disorder in which the immune system is triggered by one or more of the body's own self antigens. What causes the immune system to no longer distinguish between self and non-self antigens is unknown. One suggestion is that some microorganisms (such as bacteria or viruses) or drugs may induce some of these changes, especially in people who are genetically predisposed to develop autoimmune disorders. More than eighty such diseases have been identified and T-lymphocytes are principally involved, although some disorders are caused by B-lymphocytes. Examples include Celiac disease, Multiple sclerosis, Rheumatoid arthritis, and Type-1 diabetes. Treatment is dependent on the nature of the disease: Type-1 diabetes is addressed by the injection of the missing hormone (insulin); others may be controlled by reducing the immune system's response with immunosuppressive drugs. Allergy Allergies are very common. According to Allergy UK, one in four people in the UK suffers from an allergy at some point in their lives. The numbers are increasing every year and up to half of those affected are children. Common allergies include hay fever and eczema although, strictly, these are symptoms of an allergy to grass pollen and a substance such as latex. The most severe allergies cause anaphylactic shock, which can be rapidly fatal; although most often associated with foods, such as peanuts, or insect stings, anaphylaxis can be caused in those who are susceptible by almost any foreign substance. An allergy is an immune response to substances in the environment that are usually not harmful. The causes of allergies are both genetic and environmental. Not only has the immune system to separate self from non-self antigens, but it must not initiate a response to antigens from harmless sources such as food or pollen. For most substances this works perfectly, but, occasionally, instead of ignoring a harmless antigen, the B-lymphocytes respond to an otherwise harmless antigen and set the immune response in motion. When a person first encounters an antigen to which they are genetically susceptible, the cells that react in this sensitising exposure are B-lymphocytes. These secrete the antibody IgE (immunoglobulin E) which attaches to mast cells and activates them. A second exposure to this antigen causes the mast cells to release large quantities of histamine and cytokines which, in turn, cause symptoms such the swelling of the tissues, irritation of the eyes and nose, and, in the most severe cases, the loss of blood pressure which is known as shock.

31 TOPIC 2. SPECIFIC CELLULAR DEFENCES 25 Mast cells: Steps 1. The first time an allergy-prone person encounters an allergen such as ragweed he or she makes large amounts of ragweed IgE antibody. 3. These IgE molecules attach themselves to mast cells. 4. The second time that person has a brush with ragweed the IgE-primed mast cells release granules and powerful chemical mediators, such as histamine and cytokines. 5. These chemical mediators cause the characteristic symptoms of allergy. T- and B-lymphocytes: Questions Q9: What substances trigger the immune response? Q10: How do T-lymphocytes distinguish between self and non-self antigens? Q11: What causes an autoimmune disease?

32 26 TOPIC 2. SPECIFIC CELLULAR DEFENCES Q12: State the reaction of B-lymphocytes to being activated. Q13: What causes an allergy? 2.4 The action of T-lymphocytes Learning Objective By the end of this section, you should be able to: state that one group of T-lymphocytes destroys infected cells by inducing apoptosis; state that another group of T-lymphocytes secrete cytokines that activate B- lymphocytes and phagocytes; explain that, when pathogens infect tissue, some phagocytes capture the pathogen and display fragments of its antigens on their surface; explain that these antigen-presenting cells activate the production of a clone of T-lymphocytes that move to the site of infection under the direction of cytokines. T-lymphocytes, of which there are several types, are so-called because they mature in the thymus gland (and the tonsils). T-lymphocytes (along with phagocytes) are responsible for the cell-mediated response of the adaptive immune system. Two of these types are described here. Cytotoxic T cells Also known as Killer T cells, Cytotoxic T cells carry protein receptors on their cell membrane like all T cells. This allows them to recognise specific antigens when they come into contact with them on the surface of pathogens or cancer cells. Once attached to the target cell, they use an enzyme to perforate the wall of the cell and then inject other enzymes which induce the cell to undergo apoptosis (programmed cell death). Helper T cells As their name implies, these cells assist other white blood cells, e.g. by inducing the maturation of B-lymphocytes into plasma cells and memory B cells, and the activation of cytotoxic T cells and macrophages. Their receptors only detect antigens when they are expressed on the surface of antigen-presenting cells (APCs) such as macrophages, certain B-lymphocytes, and dendritic cells (another white blood cell type formed in haematopoietic stem cells of the red bone marrow). These APCs either engulf and digest pathogens, or they absorb the antigens which are attached to their receptors, and then display the antigens on their cell surface. Once activated, the Helper T cells divide rapidly, and then secrete the cytokines which activate B-lymphocytes and direct them along with macrophages to the site of the infection.

33 TOPIC 2. SPECIFIC CELLULAR DEFENCES 27 The action of T-lymphocytes: Questions Q14: What do Cytotoxic T Cells induce to destroy pathogens? Q15: How do antigen-presenting cells acquire the antigens which they present? Q16: What do Helper T Cells secrete to activate B-lymphocytes? Q17: What activates Helper T cells? 2.5 The action of B-lymphocytes Learning Objective By the end of this section, you should be able to: explain that B-lymphocytes are activated by antigen-presenting cells or T- lymphocytes; explain that these activated cells divide repeatedly to produce a clone of B- lymphocytes that secrete antibodies into the lymph and blood, through which they make their way to the infected area; state that each B-lymphocyte clone produces a specific antibody molecule that will recognise a specific antigen surface molecule on a pathogen or a toxin; explain that antigen-antibody complexes may inactivate a pathogen or toxin, or render it more susceptible to phagocytosis; state that in other cases the antigen-antibody complex stimulates a response which results in cell lysis. The activation of B-lymphocytes B-lymphocytes may be activated in two ways. Antigen-presenting cells, such as macrophages which have engulfed pathogens, migrate from the site of infection to the lymph nodes, where they display the antigens of the pathogen on their cell membrane. These are transferred directly to the B-lymphocytes there which carry the receptor for that antigen, so activating them. Alternatively (and more frequently), T-lymphocytes which have come into contact with the pathogens carry the foreign antigens, in combination with carrier molecules on their cell surface, to the B-lymphocytes in the lymph nodes. These antigens are likewise transferred to the receptors of the B-cells and activate them.

34 28 TOPIC 2. SPECIFIC CELLULAR DEFENCES The production of antibodies B-lymphocytes are responsible for the humoral response of the adaptive immune system. Their principal function is to produce antibodies specific to particular antigens, although some also act as antigen-presenting cells and develop into memory B cells. Antigens may either be proteins on the surface of pathogens or toxins. When activated by an antigen binding to their specific receptors, B-lymphocytes divide repeatedly by mitosis to form a clone of plasma cells. These clones are identical to the parent cells, and so all produce and release large quantities of the antibody which is specific to the antigen responsible for the initial activation. The action of antibodies Antibodies (also known as immunoglobulins) are large Y-shaped protein molecules which are released into the blood, tissue fluid or lymph. If they encounter their target antigen, they bind to it, forming an antigen-antibody complex. What follows depends on the actual antigens and pathogens involved: 1. the antibodies cluster around viruses, blocking the sites at which they bind to their host cells - in a similar fashion, antibodies may bind with bacterial toxins so rendering them harmless and identifying them to macrophages; 2. antibodies binding to the surface of bacteria may also cause them to cluster together (agglutinate); 3. some antigens are soluble and circulate in the plasma and lymph - antibodies cause these to precipitate; 4. macrophages patrolling the tissues will be attracted to pathogens and antigens which are identified by the antibodies attached to their surfaces, and remove them by phagocytosis; 5. as mentioned in an earlier section, the complement system involves over twenty plasma proteins which act in a cascade to bring about several actions as part of the innate immune system. However, the complement systems is also activated by the binding of antibodies to the antigens of pathogens and other foreign cells (e.g. red blood cells of a different blood group to the host). In this case, their effect is to create pores lined with complement proteins in the pathogen's cell membrane (known as the 'membrane attack complex'), through which fluid floods into the cell causing its lysis.